Ruby Shrestha, MD

• Department of Obstetrics and Gynecology
• Abington Memorial Hospital
• Abington, Pennsylvania

This remarkably complex process hinges on the special anatomic organization of the thymus and leads to the establishment of a T-cell repertoire capable of directing the adaptive immune response against a broad range of antigens bipolar depression quiz online order zyban 150 mg line. B-CellMaturation Although there are parallels between T- and B-cell development depression test dsm generic 150 mg zyban overnight delivery, important differences exist anxiety 8 yr old boy generic zyban 150 mg. Briefly mood disorder lesson plan buy 150mg zyban mastercard, naive cells enter primary follicles in the cortex of the secondary lymphoid tissue depression symptoms crying purchase 150mg zyban free shipping. When B-cell proliferation begins clinical depression symptoms quiz buy cheap zyban 150 mg on line, the primary follicle becomes a secondary follicle. The most common sites for microbes to breach the protective barriers of epithelium are the skin and the respiratory, gastrointestinal, and genitourinary tracts. These tissues directly encounter the outside world and possess complex, multifaceted mechanisms for dealing with antigens. It should be noted, however, that there is a vast array of nonpathogenic microbes that live in close proximity to these epithelial barriers, and an emerging body of scientific work points to the importance of these commensal organisms for maintaining immune homeostasis. Macrophages provide a critical first line of defense against pathogens by directly phagocytizing microorganisms. These signals include cytokines, nitrous oxide, and leukotrienes that cause vasodilatation, endothelial cell activation, leukocyte adhesion to endothelial cells at the inflammatory site, and diapedesis of leukocytes into the tissues (see Chapter 13). Hence the soluble and cellular components of the innate immune system provide the first line of defense at the tissues where pathogens invade. The ability of macrophages to secrete mediators that cause vasodilatation and recruitment of granulocytes, as well as initiate T-cell activation, illustrates the interplay between innate and adaptive immunity and underscores the point that the innate and adaptive immune systems work in concert in host defense. Resident T cells and plasma cells in the tissue can respond to antigen, with local activation of antigen-specific effector T cells and increased antibody secretion, respectively, so that the adaptive immune response is stimulated locally after pathogens are sensed by the innate immune system. Even in the absence of inflammation, a fraction of the fluid component of blood continually leaves the capillary bed during circulation caused by the pressure drop between the arterial and venous sides. This fluid bathes the tissues of the body picking up antigens and cells and then drains into lymphatic channels that interdigitate in every capillary bed. At sites of inflammation, the amount of fluid and cells draining into the local lymphatics increases because of changes in the vascular tone and permeability mediated by macrophage- and neutrophilderived chemokines, lipid mediators, and oxygen radicals. Lymphatic fluid eventually returns to blood circulation via the thoracic duct, which drains into the vena cava. The immune system evolved primarily to protect against invading microorganisms that penetrate the epithelial coverings of the body. In this schematic, microbes entering through a break in the skin epithelium are phagocytosed by resident macrophages as the first line of defense in innate immunity. The macrophages can secrete products that are directly microbicidal, as well as cytokines and other mediators that cause vasodilatation and endothelial cell separation, to allow influx of soluble mediators and inflammatory cells such as neutrophils and lymphocytes into the skin. Neutrophils, as a component of innate immunity, can also directly kill microorganisms, typically by releasing granular contents. Lymphocytes responding to microbial antigens proliferate and contribute to the adaptive immune response against microbes. Hydrostatic pressure across the capillary bed continually drives transudation of fluid from the blood into tissues. Fluid in lymphatics passing through chains of lymph nodes eventually collects in the thoracic duct, which returns the fluid to the vascular circulation by draining into the vena cava. The movement of lymphatic fluid through secondary lymphoid tissue is an essential component of the adaptive immune system. Lymphatic fluid in the subcapsular sinus then courses into the trabecular sinus network that runs perpendicular to the capsule through an area called the cortex. These zones are separate but contiguous compartments where B cells and T cells initially encounter antigen. Follicles are functionally characterized as either primary or secondary follicles. Some of these cell types, such as centrocytes and centroblasts, are discussed in Chapter 73 in the context of lymphoid malignancies. The modified capability of these selected B cells to generate a fast, highly specific humoral immune response upon a second encounter with the same pathogen forms the mechanistic basis of humoral memory. Memory B cells may circulate through secondary lymphoid organs and colonize the splenic marginal zone. In the lymphatic system, antigens, activated immune cells, and cytokines are kept in anatomic proximity, providing numerous opportunities for the antigens to encounter antigen-specific lymphocytes and stimulate the adaptive immune response. Moreover, in this low-pressure system, lymphatic fluid moves very slowly, thus providing a temporal as well as spatial opportunity for immune system activation. Anatomically, the direction of blood flow is opposite to that of the lymphatic fluid, which drains toward the hilum. Afferent lymphatics draining tissues enter the node on the convex side into the capsule. Fluid and cells drain through the node and collect in the medullary sinus, where the fluid leaves the node through efferent lymphatics to rejoin the lymphatic circulation. The outer rim of the node is called the cortex and contains primary follicles composed of naive, nonproliferating B cells that have not encountered antigens, and secondary follicles with proliferating B cells in the germinal center. Arterioles expand into a meshwork of capillaries within each follicle, and venous blood drains back out of the node. Naive T cells in the peripheral circulation can exit the blood and enter the lymph node through the high endothelial venules. Secondary follicles contain germinal centers filled with proliferating B cells, scattered T cells, and specialized antigen-presenting cells called follicular dendritic cells. The schematic of a section of lymph node (right) demonstrates a secondary follicle with a germinal center and a mantle zone. Scattered T cells can be found in the germinal center and are typically helper T cells that stimulate B-cell proliferation. Lymphocytes express S1P receptor-1 (S1P1) receptors that facilitate their egress from tissues into blood. Novel immunosuppressive therapeutics antagonizing S1P are being developed; these S1P antagonists reduce release of lymphocytes from lymphoid tissues into blood. The white pulp is composed mainly of lymphoid cells and is the site of antigenic stimulation of B and T cells. The red pulp consists mainly of myeloid cells, including macrophages that ingest opsonized antigens and damaged erythrocytes from the systemic circulation. The red pulp functions also as a site of extramedullary hematopoiesis early in fetal life and is a storage site for iron, erythrocytes, and platelets. In many mammalian species, including humans, splenic blood flows through a unique vascular circulation that ensures the interposing of blood (and therefore blood-borne antigens) with the lymphoid areas of the white pulp. The red pulp is the site of myeloid cells (B) that ingest and remove opsonized antigens and damaged red blood cells from the circulation. The white pulp consists of lymphoid cells, with a periarteriolar T-cell sheath and mixed B- and T-cell follicles (C). In addition to lymph nodes, this is a major site for antigen-dependent B-cell maturation and activation. The schematic of splenic anatomy (D) demonstrates how the microscopic architecture is integrated into spleen to yield a site for the interaction of the innate and adaptive immune systems. Unlike other organs that have a closed vascular circulation in which blood travels from arterial to venous circulation through capillary beds, branches of the splenic artery penetrate the white pulp, forming an open sinusoidal network termed the marginal sinuses. From the marginal sinuses, blood filters through the white pulp regions of the spleen and encounters resident B and T cells. Following this encounter, the blood is drained via branches of the splenic vein, but an efferent lymphatic circulation also collects and drains the spleen. Beyond the white pulp, the splenic artery sends additional branches into the red pulp for further blood antigen surveillance and filtration that is accomplished by macrophages. These sites provide an additional compartment of secondary lymphoid tissue where antigens can accumulate, be processed, and be presented to lymphocytes to stimulate an adaptive immune response. Belardelli F, Ferrantini M: Cytokines as a link between innate and adaptive antitumor immunity. Bottazzi B, Doni A, Garlanda C, et al: An integrated view of humoral innate immunity: pentraxins as a paradigm. Steinman L: A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Trinchieri G, Sher A: Cooperation of Toll-like receptor signals in innate immune defence. Moura-Alves P, Fae K, Houthuys E, et al: AhR sensing of bacterial pigments regulates antibacterial defence. Iwasaki A, Medzhitov R: Toll-like receptor control of the adaptive immune responses. Takahama Y: Journey through the thymus: stromal guides for T cell development and selection. Kinoshita K, Honjo T: Linking class-switch recombination with somatic hypermutation. Hayday A, Theodoridis E, Ramsburg E, et al: Intraepithelial lymphocytes: exploring the Third Way in immunology. Rawlings B lymphocytes are the subset of white blood cells specialized to synthesize and secrete immunoglobulin (Ig). Their name derives from the finding that the avian bursa of Fabricius is a site of B-cell production. Following their production in that organ, newly generated B lymphocytes migrate into secondary lymphoid organs such as the spleen where they undergo final maturation. At this point, the mature B cells may remain in the spleen or relocate via the circulation to additional tissues such as lymph nodes, where they are poised to respond to antigenic challenge. This article will focus on adult B-cell development and the regulation of that process, although we briefly discuss fetal B lymphopoiesis and its distinguishing features. The information presented provides a basis for understanding abnormalities of B-cell development such as leukemia, lymphoma, and immunodeficiency states, which are discussed in other chapters. Studies in mice have contributed much to what is known about B-cell development and have served as a basis for understanding human B lymphopoiesis. Thus, although we emphasize the human literature as much as possible, frequent reference to findings in mice are made. Finally, when Ig light chain expression occurs, the cells become surface IgM-expressing B cells. This results in gradual "specification" of progenitors towards the B-cell lineage. The processes of specification and commitment are dependent on the regulated expression of a network of transcription factors and other regulatory molecules in developing B lineage cells. For example, Ebf1 regulates the expression of Ig, VpreB, 5, and Pax5, and represses genes associated with alternative lineage fates. Lin- indicates that the cells lack expression of determinants present on mature myeloid, erythroid, and lymphoid lineage cells. Stages of human and mouse B-cell development and selected cell surface and cytoplasmic determinants that can be used to distinguish various stages of differentiation are shown. Note that there are additional cell surface and molecular determinants that can be used to define the various stages of development. After leaving the bone marrow, newly produced B cells migrate to the spleen and mature through transitional cell stages into marginal zone or follicular B cells. However, if the gene encoding Pax5 is introduced into Pax5-deficient precursors, this developmental promiscuity is no longer observed. For example, Pax5 may repress myeloid growth factor receptors, such as those for macrophage colony-stimulating factor, and inhibit the T-cell potential of lymphoid-restricted progenitors by antagonizing expression of Notch1, a cell-surface receptor whose stimulation activates signaling pathways required for commitment to the T-cell lineage. In addition to regulating commitment to the B-cell lineage, continued Pax5 expression is necessary to maintain lineage fidelity even in relatively mature B cells. Focused reviews should be consulted for a full discussion of these and additional transcriptional regulators of B lymphopoiesis. The process of Ig gene rearrangement occurs in a step-wise manner as murine and human B cells mature through the cellular stages of development just described. An increasingly accepted, second model of allelic exclusion is that the expression of heavy chain protein from a successfully rearranged allele inhibits rearrangements at the other heavy chain allele. LightChainGeneRearrangement Ig light chain protein can be encoded by the kappa or lambda genes. However, the proportions of human and proteins are more equivalent, with approximately 60% of human B cells expressing light chain protein. The human gene is located on chromosome 2 and includes around 40 V region genes, clustered in up to seven families, five functional J region genes, and one C region gene. There are seven human C genes, four of which are functional and three of which are pseudogenes. If rearrangements at the first allele are unsuccessful, attempts are made to rearrange the second gene. HeavyChainGeneRearrangement the initial Ig rearrangement events during B-cell development occur at the heavy chain locus. The Ig heavy chain locus includes multiple variable (V), diversity (D), joining (J), and constant (C) region gene segments that are separated from one another by introns. The V region genes are located at the 5 end of the Ig heavy chain locus, and each consists of approximately 300 base pairs. These genes, which are separated by short intron sequences, are organized into seven families based on sequence homology. Finally, 10 C region genes representing alternative Ig isotypes are arranged in tandem. The transcription of the unrearranged heavy chain locus occurs prior to actual Ig gene recombination.

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As cytosolic iron increases depression symptoms negative thoughts buy discount zyban 150mg on-line, concentrations of dispersed ferritin rise anxiety treatment centers cheap zyban 150 mg visa, and small clusters of ferritin begin to appear depression definition tumblr discount zyban 150mg fast delivery, still soluble and spread throughout the cytosol depression symptoms night sweats generic zyban 150 mg mastercard. With further increases in cytosolic iron depression symptoms help buy zyban now, ferritin enters lysosomes by fusion of ferritin clusters with lysosomal membranes bipolar depression and divorce 150mg zyban with amex, by autophagocytosis, or both, forming siderosomes. Production of hemosiderin seems to help protect against iron toxicity by sequestering the excess iron away from the cytosol, enclosed within siderosome membranes. Depending on the cellular type and iron supply and use, the half-life of cellular ferritin may range from less than 20 hours to 96 hours. Altogether, for short-term storage of iron, cytosolic iron is in rapid equilibrium with soluble, dispersed ferritin, but for long-term sequestration, the aggregates of iron within hemosiderin undergo slow and limited exchange. Nonetheless, with phlebotomy or iron-chelating therapy, all of the iron within hemosiderin deposits eventually can be mobilized. In the gastrointestinal lumen, dietary iron is presented to the enterocyte as heme or nonheme iron. Heme iron uptake is not well characterized, and the specific membrane transporter remains uncertain. Iron may be transported into plasma through ferroportin, regulated by hepcidin, with hephaestin or circulating ceruloplasmin acting as ferrioxidases. The enterocyte also derives iron from plasma transferrin (Tf) via the transferrin cycle (not shown). In the enterocyte cytosol, the iron can be (1) retained for cellular requirements or stored in cytosolic ferritin and then lost when the enterocyte is exfoliated or (2) exported through ferroportin on the enterocyte basolateral membrane. Iron export through ferroportin requires oxidation by membrane-bound hephaestin or circulating ceruloplasmin to the ferric form for binding by plasma transferrin. Genomic studies are needed to identify additional genes involved in the regulation of iron homeostasis. Little is known about developmental changes in the absorption, use, and storage of iron. Management of iron disposition within the systemic circulation needs further clarification, especially with respect to the basis for the dominant role of erythropoietic iron requirements and to the integration of intracellular and systemic regulatory elements. Control of iron balance needs more elucidation to determine the genetic basis for individual susceptibilities both to iron deficiency and to iron overload. More insight is needed into organ-specific iron handling and into the iron biology of specific disease states. A better understanding is needed of iron homeostasis in the three areas in the body that are outside systemic control: the central nervous system, the testis, and the retina. Nonetheless, a pivotal point has been reached when the advances already made will begin to yield therapeutic benefits from new approaches to biologic therapy using agonists and antagonists to the components of the iron regulatory pathways summarized in this chapter. Finazzi D, Arosio P: Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration. Korolnek T, Hamza I: Macrophages and iron trafficking at the birth and death of red cells. Nairz M, Schroll A, Demetz E, et al: Ride on the ferrous wheel-the cycle of iron in macrophages in health and disease. If too little iron is available (iron deficiency), limitations on the synthesis of physiologically active iron-containing compounds can have harmful consequences. The body, with no effective means to excrete excess iron, relies upon control of iron absorption to maintain homeostasis. This article focuses on the clinical application of recent remarkable progress in understanding the molecular mechanisms that preserve iron balance. Iron disorders are principally abnormalities in the amount or distribution of body iron. A fundamental advance has been the recognition that the interaction of hepcidin, the iron regulatory hormone, with ferroportin, the cellular iron export channel, is primarily responsible for the quantity and tissue disposition of body iron. Hepcidin controls iron absorption, use, and storage by binding to and inducing the degradation of ferroportin, decreasing iron entry into plasma from macrophages, hepatocytes, and intestinal enterocytes (see box on Control of Iron Homeostasis by Hepcidin and Ferroportin and Chapter 35). Hepcidin expression is suppressed with iron deficiency, hypoxia, or increased erythropoietic demand but stimulated with iron overload, inflammation, or infection. Genetic and acquired disorders with a deficiency in hepcidin production or with ferroportin resistance to hepcidin action produce iron overload. Hepcidin excess due to genetic causes produces iron-deficiency anemia, but acquired forms, such as those associated with infection, inflammation, or malignancy, result in iron sequestration and anemia. DirectMeasures the direct measures of body iron status yield quantitative, specific, and sensitive determinations of body or tissue iron stores. Quantitative phlebotomy provides a direct measure of total mobilizable storage iron. Quantitative phlebotomy is inapplicable to most anemic disorders but occasionally is useful in the diagnostic evaluation of some forms of iron overload. Bone marrow aspiration and biopsy are useful in studies of iron deficiency, but they are of limited applicability in the evaluation of iron overload because no information about the extent of hepatocyte iron deposition is provided. In the evaluation of iron overload, liver biopsy is the best direct test for assessing iron deposition, permitting quantitative measurement of the nonheme iron concentration and histochemical examination of the pattern of iron accumulation in hepatocytes and macrophages (Kupffer cells). Direct methods for assessing iron status have the disadvantages of being invasive procedures, with their attendant discomfort, lack of acceptability to patients, and, in the case of liver biopsy, risk. Body iron supply and stores can be evaluated by both direct and indirect means, but no single indicator or combination of indicators is ideal for evaluation of iron status in all clinical circumstances. In addition, each indicator may be affected by coexisting conditions that modulate hepcidin expression, such as infection, inflammation, cellular injury, malignancy, ineffective erythropoiesis, hypoxemia, liver disease, and malnutrition (see box 478 IndirectMeasures Indirect measures of body iron status have the advantages of ease and convenience, but all are subject to extraneous influences and lack specificity, sensitivity, or both. When used to estimate body iron stores, all of the available indirect measures are influenced not only by total body iron stores but also by the effects of acute or chronic changes in plasma hepcidin (see box on Control of Iron Homeostasis by Hepcidin and Ferroportin). Assays for plasma and urinary hepcidin are not yet generally available for clinical use, but they are under development and will likely be helpful in the evaluation of patients with disorders of iron homeostasis. Measurement of the plasma ferritin concentration provides the most useful indirect estimate of body iron stores. Characteristic values for some clinically available indicators of iron status are shown. In iron overload, the diagonal lines are intended to illustrate increases in excess storage iron from the normal range of 1 g or less to as much as 40 to 50 g. Under physiologic conditions, hepatic hepcidin production coordinates body iron supply with iron need. Decrements in plasma hepcidin concentration increase the amount of ferroportin, producing a rise in plasma iron concentration as a consequence of enhanced delivery from macrophages, mobilization of storage iron from hepatocytes, and increased dietary iron absorption from enterocytes. In addition to the effects of body iron stores, hepcidin production is stimulated by infection, inflammation, cellular injury, or malignancy and inhibited by hypoxemia or increased erythropoietic demand. Although hepcidin is the central regulator of iron homeostasis, hypoxia inducible factor 2 and the iron regulatory protein/iron-responsive element system modulate intestinal iron absorption (see Chapter 35). In the absence of complicating factors, plasma ferritin concentrations decrease with depletion of storage iron and increase with storage iron accumulation (see box on Plasma Ferritin Concentrations). Measurement of the plasma transferrin receptor concentration is helpful in detecting tissue iron deficiency. A majority of plasma transferrin receptors are derived from the erythroid marrow, and their concentration is determined primarily by erythroid marrow activity. While decreased levels of circulating soluble transferrin receptor are found in patients with erythroid hypoplasia (aplastic anemia, chronic renal failure), increased levels are present in patients with erythroid hyperplasia (thalassemia major, sickle cell anemia, anemia with ineffective erythropoiesis, chronic hemolytic anemia). The plasma transferrin receptor concentration reflects the total body mass of tissue receptor; thus, in the absence of other conditions causing erythroid hyperplasia, an increase in plasma transferrin receptor concentration provides a sensitive, quantitative measure of tissue iron deficiency. In particular, measurement of plasma transferrin receptor concentration may help differentiate between the anemia of iron deficiency and the anemia associated with chronic inflammatory disorders. Although the plasma ferritin concentration may be disproportionately elevated in relation to iron stores in patients with inflammation or liver disease, the plasma transferrin receptor concentration seems to be less affected by these disorders and to provide a more reliable laboratory indicator of iron deficiency. The erythrocyte zinc protoporphyrin provides an indicator of iron supply to erythroid precursors. Levels also are increased in many sideroblastic anemias and especially with chronic lead or other heavy metal poisoning. Iron stores are usually assessed on the aspirate as opposed to the biopsy because the decalcification procedure required for processing the biopsy leaches out the iron and can lead to a false conclusion of absent stores. Iron can also be seen in the cytoplasm of some nucleated red blood cells (tiny blue cytoplasmic specks), which would allow these cells to be designated sideroblasts (C). These are in contrast to red blood cell precursors with abnormal iron accumulation around the nucleus, or "ring sideroblasts" (C, inset). Hemosiderin containing iron can be seen on the Wright-stained aspirate smears as a dark brown or black pigment in histiocytes (D), but generally an iron stain is needed to confirm the presence of iron stores. When parenteral iron therapy is administered, the marrow aspirate can sometimes show coarse iron deposits, frequently in long streaks (E). This is most likely iron in endothelial cells; it does not necessarily indicate marrow iron is present. PlasmaFerritinConcentrations Plasma ferritin concentrations are helpful in the detection of both iron deficiency and iron overload. Plasma ferritin concentrations decline with storage iron depletion; a plasma ferritin concentration less than 12 mg/L is virtually diagnostic of absence of iron stores. The only known conditions that may lower the plasma ferritin concentration independently of a decrease in iron stores are hypothyroidism and ascorbate deficiency, but these conditions only rarely cause problems in clinical interpretation. Increased plasma ferritin concentrations may indicate increased storage iron, but a number of disorders may increase the plasma ferritin level independently of the body iron store. Ferritin synthesis increases as a nonspecific response that is part of the general pattern of the systemic effects of inflammation. Thus fever, acute infections, rheumatoid arthritis, and other chronic inflammatory disorders elevate the plasma ferritin concentration. Both acute and chronic damage to the liver, as well as to other ferritin-rich tissues, may increase plasma ferritin concentration through an inflammatory process or by releasing tissue ferritins from damaged parenchymal cells. After iron stores are exhausted, lack of iron limits the production of hemoglobin and other metabolically active compounds that require iron as a constituent or cofactor. A variety of mechanisms coordinate the rate of erythropoiesis with iron availability (see Chapter 35). This test is not helpful for detecting iron deficiency, owing to the overlap between values in persons with normal and those with decreased iron stores; it is used occasionally for the evaluation of iron overload. The changes are not specific for iron deficiency and may be found in other conditions with defective hemoglobin synthesis, such as thalassemia, infection, inflammation, liver disease, and malignancy. Iron overload does not produce any diagnostic abnormalities in the peripheral blood. Without iron supplementation, most women will become iron-deficient during pregnancy. Globally, half or more of the populations in many developing countries are iron-deficient, with the highest prevalence among individuals who have diets low in bioavailable iron, who have chronic gastrointestinal blood loss as a result of helminthic infection, or both. Overall, the iron requirement for an individual includes not only the iron needed to replenish physiologic losses and meet the demands of growth and pregnancy but also any additional amounts needed to replace pathologic losses. Physiologic iron losses generally are restricted to the small amounts of iron contained in the urine, bile, and sweat; shedding of iron-containing cells from the intestine, urinary tract, and skin; occult gastrointestinal blood loss; and, in women, uterine losses during menstruation and pregnancy. The median total iron loss with pregnancy is approximately 600 mg, or almost 2 mg/d over the 280 days of gestation. The most common pathologic cause of increased iron requirements leading to iron deficiency is blood loss. Within the gastrointestinal tract, any hemorrhagic lesion may result in blood loss, and the responsible lesion may be asymptomatic. Iron deficiency often is the first sign of an occult gastrointestinal malignancy or other unrecognized conditions such as coeliac disease, or autoimmune, atrophic, or Helicobacter pylori gastritis. Chronic ingestion of drugs such as alcohol, salicylates, steroids, and nonsteroidal antiinflammatory drugs may cause or contribute to blood loss. Worldwide, the most frequent cause of gastrointestinal blood loss is hookworm infection,6 but other helminthic infections, such as Schistosoma mansoni and Schistosoma japonicum, and severe Trichuris trichiura infection also may be responsible. In women of childbearing age, genitourinary blood loss with menstruation adds to iron requirements. Uncommonly, respiratory tract blood loss resulting from chronic recurrent hemoptysis of any cause produces iron deficiency. In infants, children, and adolescents, the need for iron for growth may exceed the supply available from diet and stores. With rapid growth during the first year of life, the body weights of term infants normally triple, and iron requirements are at high levels. Iron requirements decline as growth slows during the second year of life and into childhood but rise again with the adolescent growth spurt. Without supplemental iron, pregnancy entails the net loss of the equivalent of 1200 to 1500 mL of blood. In some instances, an insufficient supply of iron may contribute to the development of iron deficiency. For older children, men, and postmenopausal women, the restricted availability of dietary iron is almost never the sole explanation for iron deficiency, and other causes, especially blood loss, must be considered. Impaired absorption of iron in itself infrequently is the sole source of iron deficiency. Nonetheless, in patients in whom evaluation fails to identify a source of blood loss, as well as in those unresponsive to oral iron therapy, celiac disease, autoimmune, atrophic, or H. Increased iron requirements and an inadequate supply of iron often work in concert to produce iron deficiency. The anemia is unresponsive to orally administered iron and incompletely responsive to parenteral iron. ClinicalPresentation Patients with iron deficiency may present with (1) no signs or symptoms, coming to medical attention only because of abnormalities noted on laboratory tests; (2) features of the underlying disorder responsible for the development of iron deficiency; (3) manifestations common to all anemias; or (4) one or more of the few signs and symptoms considered highly specific for iron deficiency, namely, pagophagia, koilonychia, and blue sclerae. An uncomplicated depletion of storage iron generally is not associated with signs or symptoms, although patients without iron reserves will not respond as rapidly to an increased need for iron resulting from blood loss, growth, or pregnancy. Iron-deficiency anemia produces the signs and symptoms common to all anemias, which are pallor, palpitations, tinnitus, headache, irritability, weakness, dizziness, easy fatigability, and other vague and nonspecific complaints.

The transit through the Golgi apparatus is represented according to the cisternae progression and maturation model described in the text (4 and 5) depression test edu purchase 150mg zyban fast delivery. In the trans-Golgi the constitutive secretory pathway (6) and the regulated secretory pathway (7) separate depression definition dsm 4 quality 150 mg zyban. In specialized secretory cells mood disorder types discount 150mg zyban free shipping, selected proteins are sorted from the trans-Golgi and diverted to secretory vesicles where proteins are stored until an extracellular signal triggers their fusion with the plasma membrane and release of the content in the extracellular space (regulated exocytosis) anxiety 100 buy zyban with amex. In addition mood disorder nos symptoms diagnosis buy generic zyban from india, at the trans-Golgi proteins destined to the lysosome are sorted and delivered to the organelle through vesicles (8) anxiety wrap cheap zyban online visa. The endocytotic pathway (9) mediates the internalization of membrane or soluble extracellular proteins and their targeting to the lysosome or the recycling of some proteins to the cell surface (not shown in the figure). Proteins start to fold cotranslationally by interaction with a host of chaperones, among which is the Hsp70 family member BiP. In addition, there are folding catalysts that increase the rate of protein folding. Core oligosaccharides are further trimmed by mannosidases to produce the Man5GlcNac2 unit. Further elaboration is catalyzed by glycosyltransferases that add various sugars and create branches. This process starts with the transfer of a core oligosaccharide from a lipid-linked dolichol donor to an asparagine residue within the consensus sequence N-X-S/T of a nascent polypeptide (X can be any amino acid except for proline). The N-linked oligosaccharide is composed of a glucose3mannose9-N-acetylglucosamine2 unit (Glc3Man9GlcNac2). Many blood proteins, for example immunoglobulins, antiproteases, coagulation factors, and many membrane proteins of the cell are glycosylated. Although glycan chains are often not required for the enzymatic activity of glycoproteins, they are important for the physical properties they confer and for many physiologic functions. Glycans protect proteins from protease digestion and heat denaturation, confer hydrophilicity and adhesive properties to the proteins, and mediate interaction with other proteins or receptors. A remarkable example is the hormone erythropoietin that requires a particular complex type of N-glycan chains for its biologic function to stimulate erythropoiesis. In the recent years several studies have revealed the importance of protein N-glycosylation in promoting folding. The addition of glycan chains may prevent aggregation or provide steric influences that affect polypeptide folding and disulfide bond formation and also mediate interaction with specific chaperones. In mammalian cells, N-linked oligosaccharides are also used as signal for monitoring protein folding and trafficking. If a protein remains in its unfolded state for an extended period of time, trimming of the Man8GlcNac2 also occurs. The current model postulates that N-glycan structure generated by extensive demannosylation is the signal for glycoprotein degradation. Proteins retrotranslocate to the cytosol through a proteinconducting channel, possibly formed by derlin and/or the Sec61 complex. S1P and S2P are two important Golgi proteases as they are also involved in the regulation of cholesterol metabolism. Both the cis and trans faces are associated with tubulovesicular bundles of membranes. The processing events are temporally and spatially ordered because the processing enzymes have a characteristic distribution across the Golgi stack. In the Golgi, different types of modifications take place as for example proteolytic processing, protein O-glycosylation and elaboration of N-linked chains, phosphorylation or sulfation of oligosaccharides, and sulfation of tyrosines. The importance of protein glycosylation for human biology is underlined by the identification of many inherited human disorders that are caused by defects in these processes and cause clinical manifestations in members of families as described in Box 5. One model is retention by preferential interaction with membranes of optimal thickness. It is based on the finding that the transmembrane domains of Golgi proteins are shorter than transmembrane domains of plasma membrane proteins. These differences should allow a preferential interaction with the Golgi membrane lipid bilayer that is thinner than that of plasma membrane. Retrograde transport also serves to replenish the vesicle components lost as a result of anterograde (forward) transport. Moreover, glycosylation pathways intersect with glucose, lipid, and isoprenoid metabolism, expanding the number of players involved in these key protein modifications. Mutations affect almost every organ and some proved to block embryo development in animal models of disease. Abnormalities in N-glycosylation cause severe myasthenic syndromes caused by hypoglycosylation of the acetylcholine receptor that affects the signal transmission at the neuromuscular plaque. This would prevent the entry of proteins into the vesicles and thus their traffic to more distal cisternae. However, the mechanism whereby cargo proteins move across the Golgi complex from cis to trans remains controversial. The vesicular transport model contends that anterograde transport occurs in vesicles or tubules that traffic cargo in an anterograde direction. This alternative model proposes that Golgi cisternae are not fixed structures but move forward from the cis side to the trans side generating an anterograde movement. As cisternae mature, resident Golgi proteins that belong to more cis-like cisternae must be selectively pinched off in vesicles and trafficked back to the cis side of the Golgi stack. Although which of these models is correct is currently unclear, a majority of the experimental data supports the cisternal maturation model. In particular, technical progress in live-cell imaging provided evidence supporting a very dynamic nature of this organelle as expected by the progression/maturation model. Hurler syndrome is caused by a mutation in a hydrolase responsible for breakdown of glycosaminoglycans that prevents the hydrolase from acquiring the mannose-6-phosphate (M6P) modification, consequently preventing targeting to lysosomes. Similarly, in I-cell diseases undigested material accumulates in lysosomes because a mutation in the enzymes that create the M6P modification, causes missorting of lysosomal hydrolases. Cellular material is sequestered inside double-membrane vesicles, called autophagosomes, and degraded upon fusion with lysosomal compartments. Constitutive autophagy serves to demolish damaged organelles or cytosolic components and contributes to the maintenance of cell homeostasis. It accelerates the catabolism of cellular components to sustain the demand of energy in adverse conditions and promotes cell survival. Atg proteins are involved in the basic mechanism of autophagy on which a complex regulation has been superimposed in mammals to respond to a wider variety of hormonal, environmental and intracellular signals. An increasing body of evidence suggests that autophagy plays an important role in development and cell differentiation by facilitating cell and tissue remodeling. Remarkably, the basis for erythrocyte maturation into reticulocytes, which involves mitochondria loss, remained mysterious for decades, but is now known to be partly dependent on autophagy (mitophagy). As a consequence, defective autophagy increases susceptibility to tumorigenesis, neurodegenerative disorders, liver disease, aging, inflammatory diseases and defective host defense against pathogens. However, recent evidence suggests autophagy provides a survival advantage for tumor cells in a hostile microenvironment. The molecular basis for diversion of proteins into lysosomes and regulated secretory granules are described later. Soluble hydrolases are selectively marked for sorting into lysosomes by phosphorylation of their N-linked oligosaccharides that creates the mannose-6-phosphate sorting signal (M6P). Trafficking of these membrane-bound proteins to lysosomes is indirect, proceeding first to late endosomes or the plasma membrane before their retrieval to lysosomes. Mature secretory granules are thought to be stored in association with microtubules until the stimulation of a surface receptor triggers their exocytosis. Conjugation of a cytotoxic T cell with its target causes its microtubules and associated secretory granules to reorient toward the target cell. Subsequently, the granules are delivered along microtubules until they fuse with the plasma membrane, releasing their contents for lysis of the target cell. Endocytosis also serves to recover Chapter5 ProteinSynthesis,Processing,andTrafficking 57 the plasma membrane lipids and proteins that are lost by ongoing secretory activity. There are three types of endocytosis: (1) phagocytosis (cell eating), (2) pinocytosis (cell drinking) and (3) receptormediated endocytosis. These regulatory proteins also ensure that membrane traffic to and from an organelle are balanced. After budding, vesicles are transported to their final destination by diffusion or motor-mediated transport along the cytoskeletal network (microtubules or actin). The molecular motors kinesin, dynein and myosin have been implicated in this process. The vesicles undergo an uncoating process before fusion with the correct target membrane. Both transport vesicles and target membranes display surface markers that selectively recognize each other. Phagocytosis During phagocytosis, cells are able to ingest large particles (greater than 0. Primarily, specialized cells, including macrophages, neutrophils and dendritic cells, execute phagocytosis. Phagocytosis is triggered when specific receptors contact structural triggers on the particle, including bound antibodies, complement components as well as certain oligosaccharides. Then actin polymerization is stimulated, driving the extension of pseudopods, which surround the particle and engulf it in a vacuole called phagosome. The engulfed material is destroyed when the phagosome fuses with a lysosome, exposing the content to hydrolytic enzymes. Pinocytosis Pinocytosis refers to the constitutive ingestion of fluid in small pinocytotic (endocytic) vesicles (0. Following invagination and budding, the vesicle becomes part of the endosome system that is described later. In some cells, pinocytosis can result in turnover of the entire plasma membrane in less than 1 hour. Receptor-MediatedEndocytosis Receptor-mediated endocytosis is a means to import macromolecules from the extracellular fluid. Some receptors are internalized continuously whereas others remain on the surface until a ligand is bound. In either case, the receptors slide laterally into coated pits that are invaginated regions of the plasma membrane surrounded by clathrin and pinch off to form clathrin-coated vesicles. The endosome is part of a complex network of interrelated membranous vesicles and tubules termed the endolysosomal system. It is still a matter of debate whether these structures represent independent stable compartments or one structure matures into the next. During the formation of clathrin-coated vesicles, clathrin molecules do not recognize cargo receptors directly but rather through the adaptor proteins, that form an inner coat. For receptors that are internalized in response to ligand binding, the internalization signal may also be generated by a conformational change induced by the binding of the ligand. Protein motifs and their cognate receptors have been identified for many intracellular sorting and processing reactions. Studies are now directed to elucidate these processes at a molecular level by resolution of the three dimensional structures of the proteins involved in protein processing and trafficking. The future challenge will be to find ways of exploiting this knowledge to intervene in the numerous disease states that result from errors in these processes. Fujiki Y, Yagita Y, Matsuzaki T: Peroxisome biogenesis disorders: molecular basis for impaired peroxisomal membrane assembly: in metabolic functions and biogenesis of peroxisomes in health and disease. Fujiki Y, Yagita Y, Matsuzaki T: Peroxisome biogenesis disorders: molecular basis for impaired peroxisomal membrane assembly: in metabolic 5. In this article, we briefly outline the chemical structure of proteins and their posttranslational modifications. We explain how the properties of the 20 amino acids of which proteins are composed allow these polymers to fold into compact, functional domains and how particular domains and motifs have been assembled, modified, and reused in the course of evolution. Finally we describe a sampling of proteins and domains of relevance to the hematologist and explore briefly how point mutations, chromosomal translocations, and other genetic alterations may modify protein structure and function to cause disease. All of the amino acids share a common core or backbone structure and differ only in the "side chain" emanating from the central "-carbon" of this core. The common backbone elements include an amino group, the central -carbon, and a carboxylic acid group. Peptide bonds are formed by reaction of the carboxylic acid of one amino acid with the amino group of the next amino acid in the chain. The resonant, partial double-bond character of the peptide bond prevents rotation about this bond; thus the five main-chain carbon, nitrogen, and oxygen atoms of each peptide unit lie in a plane. The conformational flexibility in the polypeptide chain is conferred by rotation about the bonds on either side of the -carbon atom; these bond angles are referred to as phi and psi angles. The primary structure or primary sequence of a protein refers to the order in which various residues of the 20 amino acids are assembled into the polypeptide chain, and this sequence is critically important for determining the three-dimensional fold and thus function of the protein. It is the diverse chemical structure and physicochemical properties of the 20 amino acid side chains that guide the three-dimensional fold of proteins and also provide for the enormous repertoire of protein function, from catalysis of myriad chemical reactions to immune recognition, to establishment of muscle and skeletal structure. The amino acids can be divided into general classes based on the physicochemical properties of their side chains, and in particular their propensity to interact with water. Hydrophobic amino acids have aliphatic or aromatic side chains and include alanine, valine, leucine, isoleucine, proline, methionine, and phenylalanine. The hydrophobic amino acids predominate in the interior of proteins, where they are sequestered from water. They tend to pack against each other via van der Waals interactions, which contribute to the overall stability of folded protein domains. By contrast, hydrophilic, or polar, amino acids (including serine, threonine, tyrosine, asparagine, glutamine, cysteine, and tryptophan) are often exposed on the surface of proteins, where they can form hydrogen bonds with each other, with the protein main chain, and with water or ligand molecules. Hydrogen bonding refers to the attractive interaction of a proton covalently bonded to one electronegative atom (usually a nitrogen or oxygen in proteins) with another electronegative atom. Charged amino acids are also polar and are important participants in hydrogen bonding.

Estrogens cause the ductile systems to grow and branch and deposit abundant fat around them depression chinese definition order genuine zyban online. However depression symptoms in adults 150mg zyban sale, milk secretion does not begin until after birth depression diagnostic test buy 150 mg zyban fast delivery, because placental progesterone inhibits milk production and placental lactogen blocks the action of prolactin (see section 11 depression definition movement buy zyban overnight delivery. Prolactin is synthesized from early pregnancy throughout gestation depression symptoms young adults cheap zyban online amex, peaking at birth bipolar depression famous people buy cheapest zyban and zyban. Following childbirth and the expulsion of the placenta, maternal blood concentrations of placental hormones decline rapidly. In the meantime, the glands secrete a thin, watery fluid called colostrum that has more protein, but less carbohydrate and fat, than milk. Milk ejection requires contraction of specialized myoepithelial cells surrounding the alveolar glands (fig. Suckling or mechanical stimulation of sensory receptors in the nipple or areola elicits the reflex action that controls this process. Impulses from these receptors go to the hypothalamus, which signals the posterior pituitary gland to release oxytocin. Oxytocin travels in the bloodstream to the breasts and stimulates the myoepithelial cells to contract. If milk is not removed regularly, the hypothalamus inhibits prolactin secretion, and within about one week the mammary glands stop producing milk. Describe the major cardiovascular and other physiological adjustments in the newborn. Neonatal Period the neonatal (neo-natal) period begins abruptly at birth and extends to the end of the first four weeks. At birth, the newborn must make quick physiological adjustments to become self-reliant. It must respire, obtain and digest nutrients, excrete wastes, and regulate body temperature. However, the lungs of a full-term fetus continuously secrete surfactant (see section 16. For example, during the first few days of life, body temperature may respond to slight stimuli by fluctuating above or below normal levels. Similarly, the ductus venosus constricts shortly after birth and appears in the adult as a fibrous cord (ligamentum venosum) superficially embedded in the wall of the liver. The foramen ovale closes as a result of blood pressure changes in the right and left atria. As blood ceases to flow from the umbilical vein into the inferior vena cava, the blood pressure in the right atrium falls. Also, as the lungs expand with the first breathing movements, resistance to blood flow through the pulmonary circuit decreases, more blood enters the left atrium through the pulmonary veins, and blood pressure in the left atrium increases. As the blood pressure in the left atrium rises and that in the right atrium falls, the tissue flaps on the left side of the atrial septum close the foramen ovale. In most individuals the tissue flaps gradually fuse with the tissues along the margin of the foramen. In an adult, a depression called the fossa ovalis marks the site of the past opening. After this, blood can no longer bypass the lungs by moving from the pulmonary trunk directly into the aorta. In an adult, a cord called the ligamentum arteriosum forms from the remnants of the ductus arteriosus. The ability of the alveoli to exchange gases and the presence of surfactant to reduce alveolar surface tension are important. A baby born at twenty-five weeks has a 50% to 80% chance of survival to at least one year of age; at twenty-four weeks, a 40% to 70% chance; at twentythree weeks, a 10% to 35% chance; and at twenty-two weeks, a 0% to 10% chance. After birth, the metabolic rate and oxygen consumption in neonatal tissues increase. Although constriction of the ductus arteriosus may be functionally complete within fifteen minutes, the permanent closure of the foramen ovale may take up to a year. Fetal hemoglobin production falls after birth, and by the time an infant is four months old, most of the circulating hemoglobin is the adult type. Passive Aging Aging as a passive process is the breakdown of structures and slowing of function. At the molecular level, an example of passive aging is seen in the degeneration of the elastin and collagen proteins of connective tissues, causing skin to sag and muscle to lose its firmness. Another sign of passive aging at the biochemical level is the breakdown of lipids. As aging cell membranes leak during lipid degeneration, a fatty, brown pigment called lipofuscin accumulates. The cellular degradation associated with aging may be set into action by highly reactive chemicals called free radicals. A molecule that is a free radical has an unpaired electron in its outermost shell. This causes the molecule to grab electrons from other molecules, destabilizing them, and a chain reaction of chemical instability begins that could kill the cell. Free radicals are a by-product of normal metabolism and also form by exposure to radiation or toxic chemicals. Aorta Pulmonary trunk Foramen ovale (hidden by pulmonary trunk) closes and becomes fossa ovalis Ductus venosus constricts and becomes solid ligamentum venosum Liver Ductus arteriosus constricts and becomes solid ligamentum arteriosum Oxygen-poor blood Oxygen-rich blood Umbilical vein becomes round ligament of the liver (ligamentum teres) Inferior vena cava Active Aging Aging also entails new activities or the appearance of new substances. Lipofuscin granules, for example, may be considered an active sign of aging, but they result from the passive breakdown of lipids. Another example of active aging is the increased development of autoimmunity, in which the immune system turns against the body, attacking its cells as if they were invading organisms. Active aging begins before birth, as certain cells die as part of the developmental program encoded in the genes. This process of programmed cell death, called apoptosis (ayp-o-toesis), occurs regularly in the embryo, degrading certain structures to pave the way for new ones. The number of neurons in the fetal brain, for example, is halved as those that make certain synaptic connections are spared from death. Throughout life, apoptosis enables organs to maintain their characteristic shapes. As organs grow, the number of cells in some regions increases, but in others the number decreases. Or they may be concerned about inherited health conditions rather than appearances. For example, inherited gene variants that confer susceptibility to lung cancer might affect health only if a person smokes or is exposed to air pollution for many years. The field of genetics (j-netiks) investigates how genes confer specific characteristics that affect health or contribute to our natural variation, and how genes are passed from generation to generation. The two X chromosomes indicate that this size-order chromosome chart (karyotype) is from a female. Courtesy Genzyme Corporation Each chromosome except the tiny Y includes hundreds of genes. Somatic cells have two copies of each autosome, and therefore two copies of each gene. An individual who has two identical alleles of a gene is homozygous (homo-zigus) for that gene. The appearance, health condition, or other characteristics associated with a particular genotype is the phenotype (feno-tp). An allele is wild type (indicated with a plus sign) if its associated phenotype is either normal function or the most common expression in a particular population. An allele that differs from wild type has undergone a mutation, which may lead to a mutant (abnormal or unusual) phenotype. Chromosomes and Genes Are Paired Chromosome charts called karyotypes display the 23 chromosome pairs (homologous pairs) of a human somatic cell in size order (fig. Pairs 1 through 22 are autosomes (awtosomz), which do not carry genes that determine sex. The other two chromosomes, the X and the Y, include genes that determine sex and are called sex chromosomes. For many years, the first sign of a health problem was an abnormal finding on an ultrasound scan (which bounces sound waves off of an embryo or fetus and reconstructs them into an image) or results of a maternal serum screen that measures amounts of five biomarkers in the maternal circulation (see Clinical Application 2. If either or both of these approaches revealed elevated risk, then a sampling procedure was used to obtain cells from the fetus to directly check genes and chromosomes. A chromosome type present in a 50% excess number of pieces compared to other chromosome types indicates an extra chromosome-such as the trisomy 21 that causes Down syndrome. Additional tests are required to detect mutations that cause specific genetic disorders. It is likely that in the coming years, seeking clues to fetal health in the maternal bloodstream may replace the more invasive, older techniques. Due to this risk, women are advised to have the procedure only if maternal blood screening indicates increased risk of an extra chromosome or if the couple has had a child with a detectable chromosome abnormality. If the genes or chromosomes are unaffected, a tested 7-celled embryo is allowed to continue development in vitro briefly, then it is introduced into the woman. A physician uses ultrasound to guide a needle into the amniotic sac and withdraws about 5 milliliters of fluid (fig. It takes about a week to grow these cells, but a test using fluorescent dyes is used to detect the most common extra-chromosome conditions within 48 hours. Previously amniocentesis was offered only to women over age thirty-five, when the risk of conceiving a fetus with abnormal chromosomes is about 0. Some medical practices offer the test earlier in pregnancy because of the improvement in safety. After secondary If genetically healthy, the embryo is allowed to continue development, introduced into the woman and results in a baby (the remaining 7 cells can complete normal development). If the gene for the disease is present, the embryo is not introduced into the woman. Patterns in which genes are transmitted in families are called modes of inheritance. An allele that causes a trait or disease can be recessive or dominant, and inherited in either an autosomal or an X-linked manner. Y-linked conditions are extremely rare because that chromosome has very few genes. A person can inherit an autosomal recessive condition from two healthy heterozygous (carrier) parents. Or a person can inherit this condition from a homozygous recessive parent and a heterozygous parent. Three major modes of inheritance are autosomal recessive, autosomal dominant, and X-linked recessive. Cystic fibrosis illustrates autosomal recessive inheritance, in which two recessive alleles, one from each parent, transmit a trait. Because sperm and eggs combine at random, each offspring has a 25% chance of inheriting two wild-type alleles, a 50% chance of inheriting a disease-causing allele from either parent and being a carrier, and a 25% chance of inheriting a disease-causing allele from each parent. A Punnett square symbolizes the logic used to deduce the probabilities of inheriting particular genotypes in offspring. A pedigree is a diagram that depicts family members, how they are related, and their genotypes. Males are squares, females are circles, and the symbols for carriers are half filled in while those for affected individuals are entirely filled in. Geneticists use Punnett squares and pedigrees to predict the outcome in all modes of inheritance. Only one disease-causing allele is necessary to inherit an autosomal dominant condition. A Punnett square (b) and a pedigree (c) are other ways of depicting this information. Symbols in the pedigree with both black and white indicate unaffected carriers (heterozygotes). Autosomal dominant disorders tend to begin in adulthood; autosomal recessive disorders usually have an early onset. For a female, X-linked inheritance is like autosomal recessive inheritance, because she has two X chromosomes. For a male, however, recessive alleles on the lone X chromosome are always expressed. A male with an X-linked condition inherits it from a mother who is either a carrier or affected; he does not inherit an X chromosome from his father. Colorblindness and the blood-clotting disorder hemophilia A are X-linked recessive conditions. However, a mutation can originate in an individual, possibly causing a disease if it is dominant. Multifactorial Traits Nearly all inherited traits and disorders are influenced by environmental factors, such as nutrition, physical activity, and exposure to toxins and pathogens. Environmental influences are particularly noticeable for traits determined by more than one gene, termed polygenic. Usually several genes contribute, in differing degrees, toward molding the overall phenotype of a polygenic trait. Such a trait is said to be "continuously varying," which means that there are many degrees of its expression. Height, skin color, and intelligence are polygenic traits that show great variation. When individuals with a polygenic trait are categorized into classes and the frequencies of the classes are plotted as a bar graph, a bell-shaped curve emerges. Traits molded by one or more genes plus the environment are termed multifactorial, or complex. Height and skin color are multifactorial as well as polygenic, because they are influenced by environmental factors-nutrition and sun exposure, respectively.

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